Everolimus (40-O-(2-hydroxy)ethyl-rapamycin) (FIG. 1) is a synthetic derivative of sirolimus (rapamycin) that was originally isolated from Streptomyces hydroscopicus. Everolimus belongs to the class of mTOR (i.e., mammalian target of rapamycin) inhibitors and is primarily used as an immunosuppressant to prevent rejection of organ transplants and for treatment of several types of cancer including gastric cancer, renal cancer, and lymphomas.
Known methods for the synthesis of everolimus are based on alkylation of the C40-hydroxyl group of rapamycin with protected 2-hydroxyethyl fluoroalkylsulfonate 1 and subsequent removal of the protecting group from the resulting compound 2 in order to obtain everolimus (FIG. 2). The most commonly used alkylation reagent in this reaction scheme is 2-((t-butyl-dimethylsilyl)oxy)ethyl trifluoromethanesulfonate (1a in FIG. 3). Compound 1a is usually obtained by means of a rather complex two-step synthesis scheme starting from ethylene glycol (FIG. 3) Due to its high instability it has to be used immediately after preparation.
The pharmacological activity of everolimus as well as a method for its manufacture was initially described in WO 94/09010 A1. Here, synthesis is accomplished by reacting rapamicyn with 4 equivalents of 2-((t-butyldimethylsilyl)oxy)ethyl trifluoromethanesulfonate in toluene at 60° C. using 2,6-lutidine as a base in order to obtain 40-O-[2-(t-butyldimethylsilyl) oxy]ethyl-rapamycin. The product is purified by chromatography and deprotected using 1N HCl in methanol. The resulting crude everolimus is then again purified by chromatography. However, the overall yield of final product, as described in WO 2012/103959 A1, is only at about 17%.
The use of a t-butyldiphenylsilyl protective group was suggested by Moenius and coworkers (Moenius, T. et al. (2000) J. Labelled Cpd. Radiopharm. 43, 113-120 (2000)) with regard to the synthesis of tritiated everolimus. The process employs 2-(t-butyldiphenylsilyl)oxyethyl triflate in a mixture of toluene-dimethoxyethane at 50° C. using N,N-diisopropylethylamine as a base. However, the overall yield of everolimus obtained after subsequent deprotection was also very low.
WO 2012/066502 A1 discloses the synthesis of everolimus by reacting rapamycin with an excess of 4-8 equivalents of 2-(t-butyldimethylsilyl)oxyethyl triflate, using dichloromethane, ethyl acetate or toluene as a solvent and 2,6-lutidine as a base, followed by deprotection of the obtained t-butyldimethylsilyl-everolimus derivative. An overall yield of final product of about 45% was obtained by performing the reaction in dichloromethane and using 8 equivalents of alkylator.
The method disclosed in WO 2012/103959 A1 relates to the alkylation of rapamycin with the more stable 2-(t-hexyldimethylsilyl)oxyethyl triflate. The reaction is carried out at 70° C. with 4 equivalents of 2-(t-hexyldimethylsilyl)oxyethyl triflate in a mixture of toluene-dimethoxyethane and using N,N-diisopropylethylamine as a base. Further deprotection of the silyl group with 1N HCl in methanol results in the formation of everolimus in slightly improved overall yield (about 52%) as compared to previous methods.
However, the method of WO 2012/103959 A1 is hampered by the complicated preparation of the starting 2-(t-hexyldimethylsilyl)oxyethyl triflate. It requires purification of the product of the first reaction step, 2-((2,3-dimethylbut-2-yl)dimethylsilyloxy) ethanol, by fractional vacuum distillation, performing the second reaction step at low temperatures (−30° C.), and the requirement of an additional purification of the crude 2-(t-hexyldimethylsilyl)oxyethyl triflate. Furthermore, the method has to be performed at high temperature (70° C., cf. above), which greatly increases the probability of undesirable side reactions and of impurities being present in the crude product. Hence, chromatography purification of protected everolimus derivative is required as additional step before the purified product can be subjected to the deprotection step.
WO 2014/203185 A1 discloses the use of sterically hindered amines as bases in the synthesis of everolimus comprising reacting rapamicyn with a compound 1 (cf. FIG. 2) and removal of the protection group to obtain everolimus. The use of amines, such as N,N-diisopropylpentane-3-amine, diisopropylnonane-5-amine and N,N-diisobutyl-2,4-dimethyl-pentan-3-amine, as a base during the alkylation of rapamycin increases the stability of the alkylator 1, which results in an improved yield of everolimus. An overall yield of crude everolimus of about 67% was obtained when performing the reaction in toluene at 40° C. and using 2.5 equivalents of 2-(t-butyldiphenylsilyl)oxyethyl triflate and N,N-diisopropylpentane-3-amine as bases. However, the starting material 2-((t-butyldiphenylsilyl)oxy)ethanol that is to be employed for the preparation of the triflate compound as well as any of the above mentioned sterically hindered amines are not commercially available and difficult to prepare, which is a major drawback of this process.
Hence, there is still an ongoing need for improved methods for the synthesis of everolimus that overcome the limitations of the established synthesis routes.
In particular, there is a need for a less laborious and cost-efficient method for the preparation of 2-(tri-substituted silyl)oxyethyl triflate, thus also improving the overall yield of the synthesis of everolimus, starting from rapamycin, while minimizing the formation of undesired by-products.
Accordingly, it is an object of the present invention to provide an improved method for the synthesis of everolimus.